HBV in HIV Forgotten but not Gone

Richard K. Sterling, MD, MSc

VCU Hepatology Professor of Medicine

Chief, Section of Hepatology

Virginia Commonwealth University

Objectives

• Natural history of HBV

• Diagnosis of HBV

– Understanding serologies

• Definitions and terminology

• Epidemiology of HBV in HIV

– Prevalence, presentation, natural history

• Treatment of HBV in those with HIV

– In those who require ART and those that do not

Phases of Chronic HBV Infection

Diagnosis of HBV

Surface Core DNA

Ag Ab IgM IgG E Ag E Ab

Acute + - + - + - +

Window - - + -/+ - + -

Resolved - + - + - + -

Chronic

Active + - - + + - +

Inactive + - - + - + -

Pre-core + - - + - -/+ +

Vaccinated - + - - - - -

HBV Pre-core Mutation

Wild HBV Pre-core Core

E Ag Core Ag

Pre-core mutation

X

Core Ag

Only Core Ag needed for viral replication

Definitions Definition Diagnostic criteria

Chronic HBV

HBeAg + / HBeAb -

HBeAg - / HBeAb +/-

Surface antigen + > 6 months

HBV DNA > 2,000 IU/ml

Abnormal AST/ALT

Active histology

Inactive chronic HBV Surface antigen + > 6 months

HBeAg negative/ HBeAb positive

HBV DNA < 2,000 IU/ml

Normal AST/ALT

Inactive histology (but may have

advanced fibrosis)

Resolved HBV Surface antigen negative/sAb +

HBV DNA negative

Normal AST/ALT

Chronic HBV: Terminology

• Seroconversion: Converting from HBeAg+ to HBeAg-negative and anti-HBe+ or conversion from HBsAg + to HBsAb +

• Reversion: Reappearance of HBeAg in carriers who were HBeAg-neg/anti-HBe+

• Exacerbation: Elevation of aminotransferase levels in carrier with normal levels (usually defined as 2X to 4X elevation)

Hepatitis D

• Coinfection

– More severe acute hepatitis

– Less chronic infection

• Superinfection

– Exacerbation of chronic HBV

– Increased progression to cirrhosis

– Increased hepatic decompensation

– Increased risk of HCC

Prevalence of Disease

HBsAg+ HIV+

400 million

40 million

Coinfected: 4 million

• 90% of those with HIV have

Markers of past HBV exposure

• 8-10% have chronic infection

Prevalence of chronic hepatitis B virus infection among patients

in the HIV Outpatient Study, 1996–2007†

Journal of Viral Hepatitis 2010;17:879-886

Impact of HIV on HBV • Less likely to resolve acute HBV infection

– Bodsworth et al. JID 1991;163:1138

– Gilson et al. AIDS 1997;11:567

• Increased chance of reactivation and flares – Vento et al. Lancet 1989;2:108

– Lazizi et al. JID 1988;158:666

• Immune reconstitution syndrome

• Increased HBV DNA – Colin et al. Hepatology 1999;29:1306

• Increased risk of cirrhosis – Thio et al. Lancet 2002;360:1921

• Increased overall mortality (even with HAART) – Thio et al. Lancet 2002;360:1921

– Nikolopoulos et al. CID 2009;48:1763-71

– Hoffmann CJ et al. AIDS 2009;23:1881-1889

HIV negatively impacts on HBV Multicenter AIDS Cohort Study

• 5293 men

0

2

4

6

8

10

12

14

16

HIV-HBV HIV HBV

Liv

er

rela

ted m

ort

alit

y/1

000

pers

on y

ears

N=213 N=2346 N=139

Highest with lower nadir CD4

Higher after 1996 (HAART) Thio et al. Lancet 2002

Factors associated with Death

Factor Adjusted RR 95% CI

Age (per 5 yrs) 1.16 1.09-1.24

IVDU (MSM reference) 5.02 3.56-7.08

HTN 2.34 1.83-2.99

Diabetes 2.37 1.68-3.35

HCV 1.67 1.21-2.31

HBV 2.37 1.74-3.22

CD4 count/50 cell

increase

0.82 0.79-0.85

HIV RNA >100,000

copies

1.68 1.01-2.80

D:A:D Study AIDS 2010;24:1537-1548

Liver disease outcomes

N= 72 Yes

(n=7)

No

(n=65)

p

Baseline ALT 105 52 .002

HBV DNA negative % 57 45 0.7

HBeAg negative% 33 16 0.4

HCV+ % 28 8 0.1

CD4 nadir 80 176 0.2

ART duration (yrs) 2.8 1.7 0.2

• Followed 1990-2008

• Median f/u 3 yrs (IQR 1-6)

• 64/72 (89%) on HBV-active

HAART

• 7 developed cirrhosis

• 3 died

• 2 with HCC had negative

HBV DNA and HIV RNA

Lee et al. HIV Clin Trials 2009

Comparison of HBV and HIV-HBV Co-infected

Patients: Analysis of the HBRN Screening Log

• As of 9/17/2012, 5966 HBsAg positive adult patients (age >18) who attended clinics were screened.

• Demographic and the most recent clinical and laboratory data were collected. Although some laboratory data were current from the day of the clinic visit, many such as HBV DNA and HBV serology results were usually from the prior clinical assessment.

• Those with HIV co-infection were compared to those with HBV alone.

Sterling et al

Unpublsihed

Results

• Patient characteristics of the screened patients were as follows:

– 1491 (72%) HBeAg positive (missing 610)

– 2469 (41%) female

– 69.2% Asian, 17.2% White, 12.3% Black, and 1.3% other (self-reported race information missing on 246 patients)

– median age was 47 years

– Of the 5957 patients with information on HIV status, 149 (2.5%) were HIV positive.

Results: HIV-HBV Patients (n=149)

Characteristic n %

Sex (male/female) 135/14 90.6/9.4

Race

(White/Black/Asian)

82/52/7 57.3/36.4/4.9

Age at screen (years)

18-30 3 2.0

31-40 17 11.4

41-50 69 46.3

51-60 47 31.5

>61 13 8.7

HBeAg (+/-) 81/55 59.6/40.4

Comparing HIV+ to HIV - Characteristics HIV Positive

(n=149)

HIV Negative

(n=5808)

p

Age [years, median (25th,

75th)]

49 (44, 54) 47 (36, 57) 0.059

Male (n, %) 135 (90.6) 3358 (57.8) <0.0001

ALT [IU/L, median (25th, 75th)] 36.5 (24.0,

61.0)

30.0 (21, 45) 0.001

HBeAg positive (n, %) 81 (59.6) 1407 (27.0) <0.0001

HBV DNA negative (n, %) 68 (50.4) 1696 (33.4) <0.0001

On anti-HBV Rx (n, %) 117 (78.5) 2337(40.3) <0.0001

History of HCC (n, %) 2 (1.3) 160 (2.8) 0.44

History of decompensation (n,

%)

15 (10.1) 144(2.5) 0.001

History of liver transplantation

(n, %)

0 (0) 51 (0.8) 0.64

Age Distribution by HIV Status

0

5

10

15

20

25

30

35

40

45

50

18-30 31-40 41-50 51-60 61+

HIV +

HIV -%

Age in years

P<.0001

Race Distribution by HIV Status

0

10

20

30

40

50

60

70

80

Asian Black White Other

HIV +

HIV -%

P<.0001

HBV DNA Status by HIV Status

and HBV Treatment Status

0

10

20

30

40

50

60

70

80

90

100

HBeAg - HBeAg+ HBeAg- HBeAg+

Not on Rx

On Rx

HIV Positive HIV Negative

% B

elo

w d

ete

cta

ble

HB

V D

NA

Predictors of Histology All

(n=53)

Stage 0-2 (n=22) Stage 3-4 (n=31) p

Age 42(10) 43(9) 41(10) .63

Gender (% male) 96 100 90 .26

Race (%W/AA/O) 64/30/6 64/18/18 61/39/0 .03

ART (%) 66 45 81 .02

HBV Rx

TDF/FTC

TDF

LAM

32

9

28

32

0

23

32

16

32

.11

HBeAg + (%) 62 59 65 .76

HDV + (%) 6 9 3 1.0

HIV Stage (% A/B/C) 57/9/34 79/0/21 43/14/43 .14

HIV RNA

undetectable (%)

63 46 74 .15

HIV-HBV Research Network; EASL 2013

Predictors of Histology All

(n=53)

Stage 0-2 (n=22) Stage 3-4 (n=31) p

CD4 420(288) 496(368) 389(284) .08

AST 52(68) 47(30) 65(131) .08

ALT 57(73) 54(48) 65(106) .35

APRI 0.8(1.2) 0.5(.9) 1.2(1.5) .02

FIB-4 1.8(1.5) 1.7(1.0) 1.9(2.8) .16

HBV DNA < 1000

IU/ml

16(35) 5(23) 11(39) .53

HBV DNA

undetectable

14(30) 5(28) 9(32) .51

HIV RNA negative 20(63) 6(46) 14(74) .15

HIV-HBV Research Network; EASL 2013

Treatment of HBV in the setting of HIV

Treatment Candidates

• Active infection (S Ag +)

– + E Ag or HBV DNA > 20,000 IU/ml

– Necroinflammation / elevated ALT

– True HBV DNA cut off not known

– Cirrhosis (detectable HBV DNA)

• Compliant

• Need to decide which virus needs

treatment: HBV, HIV, or both

Goals of therapy

• Overall goals

– Loss of active replication • E Ag seroconversion

• Loss of HBV DNA

– Improve necroinflammation

– Reduce liver related mortality

• Goals unique to those with HIV

– Reduce ARV hepatotoxicity

– No interference with HIV therapy

Treatment Options Drug HBV HIV

Interferon Yes No

Lamivudine Yes Yes

Tenofovir Yes Yes

Emtricitabine Yes Yes

Adefovir Yes No

Entectavir Yes No (?)

Treatment Decisions

Virus needing treatment Preferred regimen Drugs to avoid

HBV only PEG-IFN Monotherapy with

Adefovir (?) LAM, FTC, TDF, Ent

HIV only Consider reserving Use of LAM, FTC,

LAM, FTC, TDF or TDF as only

anti-HBV Rx in

HAART

HIV and HBV

Naïve to LAM TDF and FTC or Use of LAM, FTC,

LAM or TDF as only

anti-HBV Rx in

HAART

Prior LAM TDF and FTC

Entecavir (higher dose)

Modified from CL Thio. Current Hepatitis Reports 2004;3:91-97

Proposed Algorithm HBV-HIV Coinfection HBV SAg+

HBV DNA, ALT

HBV E Ag / E Ab

HBV EAg -

HBV DNA < 103 HBV DNA > 103

Nl ALT Elev ALT

Follow

R/O other Cause (HCV,

HDV, EtOH, NAFLD)

HBV EAg +

No HIV Tx

needed HIV

needed

HBV DNA < 2000

& Normal ALT

HBV DNA > 2000

Or elevated ALT

Monitor

q 3 mo PEG-IFN

(ADV)

Start HAART

w/TDF +LAM/FTC

Pre-core mutant

LBx

Proposed Algorithm HBV-HIV Coinfection HBV SAg+

HBV DNA, ALT

HBV E Ag / E Ab

HBV EAg -

HBV DNA < 103 HBV DNA > 103

Nl ALT Elev ALT

Follow

R/O other

Cause (HCV, HDV)

HBV EAg +

No HIV Tx

needed

HIV

needed

HBV DNA < 103

& Normal ALT

HBV DNA > 103-4

Or elevated ALT

Monitor

q 3 mo PEG-IFN

(ADV)

Start HAART

w/TDF +LAM/FTC

Pre-core mutant

LBx

Treat all coinfected

patients

with TDF +

FTC/LAM based

ART regardless of

CD4 or HIV RNA

Kaplan-Meier curve for the cumulative probabilities of achieving virologic

response, defined as HBV-DNA levels less than 20 IU/mL, for HBeAg-positive (n =

67) and HBeAg-negative (n = 15) HIV/HBV with patients with detectable HBV DNA

at baseline (n=82)

Theodora E.M.S. de Vries-Sluijs et al

Gastroenterology Volume 139, Issue 6 2010 1934 - 1941

Long-term Therapy With Tenofovir Is Effective for Patients

HIV-HBV Co-Infected based HBeAg status

Non-response

- 13% eAg+

- 7% eAg -

82 HBV DNA+

66% Caucasian

15% cirrhosis

CD4 285

HBeAg+ 82%

Kaplan-Meier curve for the cumulative probabilities of achieving virologic

response, defined as HBV-DNA levels less than 20 IU/mL, for HIV/HBV patients

with detectable HBV DNA at baseline (n = 82) with (n=33) or without (n=49)

lamivudine-resistant at initiation of TDF

Long-term Therapy With Tenofovir Is Effective for Patients

HIV-HBV Co-Infected based LAM Resistance

Gastroenterology Volume 139, Issue 6 2010 1934 - 1941

Summary of TDF for HBV in HIV Lada Miailhes Sheng Mathews Piroth De Vries Martin-

Carbonero

Year 2011 2007 2007 2009 2010 2010 2010

N 61 92 119 122 180 102 92

CD4 290-

381

303 125 438 401 300

% HCV/HDV 10/13 13/0 9/0 0/0 >12%/

0

0/0 0/20

F/U (yrs) 5 5 5.2 2 3.5 4.5 3

% HBV DNA

negative on Rx

82-

100

30 TDF

77

TDF/FTC

87 92-

100

89

%HBeAg loss 4.3/yr 10/yr 9/yr

% HBeAb

seroconversion

4.4/yr 3.4/yr 0.9/yr 2.6/yr

Patient Evaluation • History and Physical

– Attention to signs/symptoms of advanced fibrosis

• Laboratory testing

– Viral tests (HBV DNA, HBeAg/Ab, genotype?)

– HCV, HDV, HAV

– Liver chemistries, prothrombin time

– CBC with platelets

– In those with chronic HBV (sAg+) • Ultrasound +/- AFP (HCC screening)

• Consider Liver biopsy

Recommendations to Patients

• Avoid alcohol

• Hepatitis A vaccination (if anti-HAV neg)

• Counsel on sexual transmission

• Test all household contacts

– Vaccinate if negative

• Cover open cuts

• Clean up blood spills with bleach

• Perinatal counseling

– HBIG and vaccinate newborn

• Avoid raw shellfish/seafood (vibrio)

Unresolved Issues in HIV-HBV

• Role of liver biopsy

• Noninvasive assessments of disease

severity

• Incomplete responders

• Use of novel assays (qHBsAg)

• Isolated core antibody

• Long-term effects of TDF (renal and bone)

• Liver transplantation

Thank you for your attention